Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH:44]([CH:56]=O)[CH2:45][C:46]2[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=2)=[CH:38][CH:37]=1)#[N:35].O>CCCCCC.C1COCC1>[C:34]([C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][CH:44](/[CH:56]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][C:46]2[CH:47]=[CH:48][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:54][CH:55]=2)=[CH:40][CH:41]=1)#[N:35]
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C=O)CCc2ccc(C#N)cc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.3 %

Procedure:
9.39 ml (15.02 mmol) of a 1.6 M solution of n-butyllithium in hexane are slowly added to a solution of 2.459 g (5.36 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 65 ml of anhydrous THF at 0° C. Then, at this temperature, 1.744 g (5.36 mmol) of methyl 4-[4-(4-cyanophenyl)-2-formylbutyl]benzoate from Example 16A, dissolved in 65 ml of THF, are slowly metered in. After warming to room temperature, the reaction solution is stirred for 12 hours and then, after addition of some water, concentrated to dryness. The resulting residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 1.44 g (3.50 mmol, 65% yield) of a colorless solid are obtained.
Reaction SMILES: FC(F)(F)C1C=CC(C(O)=[O:8])=CC=1.C[C:15]1[CH:16]=[CH:17][C:18]([O:24][C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[C:19]2[C:23]=1[CH2:22][CH2:21][CH2:20]2>>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:18]2[CH:17]=[CH:16][CH:15]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:8])=[N:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1CCC2
Product: Nc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
According to the same manner as that described in Example 1 except for using an equimolar amount of 4-(trifluoromethyl)benzoic acid in place of 3,4-dichlorobenzoic acid and using an equimolar amount of 6-[(7-methyl-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinylamine obtained in Reference Example 29 in place of 4-[(5-amino-2-pyridinyl)oxy]-1-indanone, the reaction was carried out to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH2:46])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[CH2:26]([O:33][C:34]1[C:43]2[C:38](=[C:39]([CH2:44][CH2:45][NH:46][C:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: NCCc1cccc2c(OCc3ccccc3)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1cccc2c(OCc3ccccc3)cccc12)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a solution of diphenylacetic acid (0.171 g) in methylene chloride (10 ml), dimethylaminopyridine (0.01 g) and 1-benzyloxy-5-(2-aminoethyl)naphthalene (0.196 g) were added at room temperature. After 10 minutes, EDC·HCl (0.154 g) was added to the mixture solution. The mixture was stirred overnight at room temperature for 1 night. After termination of reaction, water and methylene chloride were added to the reaction mixture. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and a saturated aqueous solution of sodium chloride, dried over and concentrated under reduced pressure. The residue was purified on silica gel chromatography to give the title compound (0.172 g) having the following physical data.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[N:15]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CC(C)COC(=O)n1c(CN2CCN(c3ccccn3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a stirred solution of Example 1A (0.77 g, 2.6 mmol) in dichloromethane (7 mL) was added isobutyl chloroformate (0.375 mL, 2.9 mmol). The mixture was stirred at room temperature for 16 hours, concentrated under reduced pressure and the residue was purified by flash column on SiO2 eluting with 1.3% methanol/dichloromethane to give 0.5 g (49%) of the title compound as an oil. 1H NMR (CDCl3, 300 MHz) δ 1.10 (d, J=6 Hz, 6H), 2.22 (m, 1H), 2.86 (bm, 4H), 3.67 (bm, 4H), 4.18 (bs, 2H), 4.33 (d, J=7 Hz, 2H), 6.66 (m, 2H), 7.35 (m, 2H), 7.53 (m, 1H), 7.76 (m, 1H), 7.93 (m, 1H), 8.19 (m, 1H). MS (DCI/NH3) m/z 394 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1.I[C:34]1N(COCC[Si](C)(C)C)C(C2(OC)COC2)=NC=1C.IC1N(COCC[Si](C)(C)C)C(C2(O)COC2)=NC=1C>>[CH3:34][O:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:18][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:20]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:3][O:4][CH2:5]1
Reactant: COC1(c2nc(C)c(I)n2COCC[Si](C)(C)C)COC1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Agent: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Product: COC1(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 192, except 5-iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 194.1) was used in place of 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3). m/z (ES+) 443 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([OH:21])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:33]1([CH3:40])[CH:38]=[CH:37][C:36](Cl)=[CH:35][CH:34]=1>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[C:10]([O:21][C:36]2[CH:37]=[CH:38][C:33]([CH3:40])=[CH:34][CH:35]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)CC(=O)Oc1ccc(C(=O)CNC(C)C)cc1O
Reactant: Cc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2cc(C(=O)CNC(C)C)ccc2OC(=O)CC(C)C)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted wirh p-toluyl chloride there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(p-toluyloxy)-4-(isovaleryloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([NH:16][CH:17]=O)[CH2:3]1.CO.Cl.O>O1CCCC1>[CH3:17][NH:16][C:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=1
Reactant: O=CNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 10 °C

Procedure:
4,5-Dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl formamide (39.6 g, 129.2 mmole) was dissolved in dry tetrahydrofuran (500 ml) with warming and then cooled to 10° C. with stirring. Borane dimethylsulfide complex (10M, 80 ml, 800 mmole) was added dropwise by syringe through a septum cap. The reaction mixture was heated on a steam bath for ca 12 hrs (overnight), cooled in an ice bath, methanol (150 ml) added dropwise and the mixture stirred for 1 hr until the effervescence had subsided. Concentrated hydrochloric acid (30 ml) was then added to give a clear solution. This was poured into water (51) and extracted with ethyl acetate (×2) and the extract washed and dried (MgSO4). Evaporation of the solvent left a white glass which was dried under vacuum for 2 hrs. The yield of product was 33.4 g, 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][Cl:34])=[CH:46][CH:45]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCl)cc3)c3c(Cl)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-(2-chloroethyloxy)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 499/501 (M+NH4). 1H-NMR (DMSO-d6) δ 3.24 (td, J=9.2, 4.1 Hz, 1H), 3.39 (td, J=8.7, 5.2 Hz, 1H), 3.43-3.47 (m, 2H), 3.62-3.69 (m, 2H), 3.91-3.93 (m, 2H), 4.19-4.21 (m, 4H), 4.53 (t, J=4.9 Hz, 1H), 5.09 (d, J=4.8 Hz, 1H), 5.15 (d, J=4.7 Hz, 1H), 5.21 (d, J=5.3 Hz, 1H), 5.39 (d, J=9.2 Hz, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.02 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 7.22 (s, 1H), 7.53 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:39]3[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:7]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C2CCNCC2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C2CCNCC2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-piperidin-4-ylphenyl)indole-3-carboxylic acid ethyl ester (203 mg, 0.45 mmol, see step (b) Example 17) and 4-trifluoromethylphenylboronic acid. Yield 160 mg (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[Cl:21][CH:22]([CH3:26])[C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH:22]([CH3:26])[C:23]([NH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])=[O:24]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Cl)C(=O)NCCc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.9 %

Procedure:
A solution of 2,4-dichlorophenethylamine (1.0 g, 5.3 mmol) in dichloromethane (20 mL) was treated with diisopropylethylamine (0.82 g, 6.3 mmol) and 2-chloropropionylchloride (0.67 mL, 5.3 mmol) sequentially, and stirred at 20° C. for 4 hours. The mixture was diluted with dichloromethane (50 mL), washed with 10% aqueous HCl, brine (20 mL), dried with Na2SO4 and concentrated, resulting in 1.5 g of the desired product as a brown oil. MS calculated for C11H12Cl3NO+H: 280, observed: 280.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2SC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[N:43]1([C:49]2[S:50][CH:51]=[C:52](CN)[N:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[N:4][C:5]([NH:8][CH2:9][C:52]2[N:53]=[C:49]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[S:50][CH:51]=2)=[N:6][CH:7]=1
Reactant: NCc1csc(N2CCOCC2)n1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2csc(N3CCOCC3)n2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with 1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH3:14])([O-:3])=[O:2].C(O)=O>[Pd].C(N(CC)CC)C.C(OCC)(=O)C>[CH3:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([CH3:10])[CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 2,6-dinitro-m-xylene (11.2 g) and 10% palladium on charcoal (620 mg) was stirred in triethylamine (36 mL) under an atmosphere of nitrogen and heated to reflux. Formic acid (9.25 mL) was added dropwise to the above mixture with vigorous stirring. After addition, the mixture was allowed to stir at reflux for an additional 15 min, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through celite. The filtrate was washed with brine and dried over magnesium sulfate. Evaporation afforded 9.51 g as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1NO.[OH:28][N:29]1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:29][O:28][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[O:17])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(CCCCc2ccccc2)cc1
Reactant: ONC1CCCCO1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccc(CCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-(4-phenylbutyl)benzoic acid (700 mg, 2.8 mmol) in 40 ml of CH2Cl2 under argon was added tetrahydropyranyl hydroxylamine (H2N-OTHP) (654 mg, 2.0 eq.), 1-hydroxybenzotriazole (HOBt) (460 mg, 1.2 eq.), N,N'-dicyclohexylcarbodiimide (700 mg, 1.2 eq.) sequentially. After 0.5 hour at 0° the solution was allowed to warm to room temperature and stir under argon for 4 hours. The solution was filtered, concentrated in vacuo to yield a white solid which was chromatographed on LPS-1 silica gel eluting with 6:4 hexane/EtOAc. Product containing fractions were evaporated to give title compound, an oil 1.0 g (~100%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23](N)=[CH:22][C:21]=2[O:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:25]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][C:27]=2[O:28][CH2:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCO5)c3c2s1
Yield: 49 %

Procedure:
Prepared from VII and 3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 9:1). Yield: 49%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 2894, 2226, 1734, 1706, 1645, 1609, 1581, 1555, 1499, 1471, 1377, 1354, 1304, 1264, 1236, 1211, 1188, 1162, 1125, 1086, 1037, 972, 938, 924, 859, 829, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.14 (m, 1H), 7.76 (m, 1H), 6.94 (d, 2H, J=9.0 Hz), 6.72 (m, 1H), 6.02 (s, 2H); HRMS calcd for C17H9N5O2S (M+H+): 348.0555, found 348.0566.
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14](=[O:47])/[C:15](/[N:20]1[CH:23]([S:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]1=[O:46])=[C:16](/[O:18][CH3:19])\[CH3:17].COC(=O)/C(/N1C(SS(C2C=CC(C)=CC=2)(=O)=O)C(NC(=O)COC2C=CC=CC=2)C1=O)=C(\OC)/C>O1CCCC1.C(Cl)Cl>[CH3:12][O:13][C:14]([C@@H:15]1[N:20]2[C:21](=[O:46])[C@@H:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:23]2[S:24][CH:17]=[C:16]1[O:18][CH3:19])=[O:47]
Reactant: COC(=O)/C(=C(\C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Agent: COC(=O)/C(=C(/C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12

Procedure:
302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to a solution of 534 mg (1 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel using toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8.25μ, followed by pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90 and 7.10μ, in the form of colourless foams.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(Cl)Cl>O1CCCC1>[C:25]([NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10])(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium acetate (50% in water, 29 ml) was added in three portions to a stirred solution of 2-amino-4′-benzyloxyacetophenone HCl (4.6 g, 17 mmol) and tetrahydrofuran (200 ml). Palmitoyl chloride (19 mmol) in tetrahydrofuran (25 ml) was added dropwise over 20 min yielding a dark brown solution. The mixture was stirred overnight at room temperature. The aqueous fraction was removed by use of a separatory funnel and chloroform/methanol (2/1, 150 ml) was added to the organic layer which was then washed with water (50 ml). The yellow aqueous layer was extracted once with chloroform (50 ml). The organic solutions were then pooled and rotoevaporated until near dryness. The residue was redissolved in chloroform (100 ml) and crystallized by the addition of hexane (400 ml). The flask was cooled to 4° C. for 2 h. The crystals were filtered and washed with cold hexane and dried in a fume hood overnight. The product yield was 3.79 g (8 mmol). An Rf of 0.21 was observed when resolved by thin layer chromatography using methylene chloride. [M+H]+: 479 for C31H45NO3. 1H nmr (δ, ppm, CDCl3), 7.96 (2H, δ, 8.8 Hz, O—Ar—C(O)), 7.40 (5H, m, Ar′CH2O—), 7.03 (2H, δ, 8.8 Hz, O—Ar—C(O)), 6.57 (1H, bs, NH2), 5.14 (2H, s, Ar′CH2O—), 4.71 (2H, s, C(O)CH2NHC(O)), 2.29 (2H, t, 7.4 Hz, C(O)CH2(CH2)13CH3), 1.67 (2H, m, C(O)CH2(CH2)13CH3), 0.87 (3H, t, 6.7 Hz, C(O)CH2(CH2)13CH3).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH:30]1[C:39]2[C:34](=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1>>[CH:30]1[C:39]2[C:34](=[C:35]([N:40]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]6)(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:41]3)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: NNc1cccc2cnccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCCC3)c2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(piperidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-26) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=513.4 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH:10]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:22])([CH3:23])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (6.4 g, 15 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (10 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (5% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (2.51 g, 41%) as a white solid: LC/MS m/e calcd for C19H19BrClNO2 M+: 408.7, observed: 408.8.